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WO2009031877A1 - Composition pharmaceutique comprenant une combinaison d'acémétacine, de méthocarbamol et de diacéréine, utile dans le traitement de l'arthrite rhumatoïde et des maladies associées - Google Patents

Composition pharmaceutique comprenant une combinaison d'acémétacine, de méthocarbamol et de diacéréine, utile dans le traitement de l'arthrite rhumatoïde et des maladies associées Download PDF

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Publication number
WO2009031877A1
WO2009031877A1 PCT/MX2008/000118 MX2008000118W WO2009031877A1 WO 2009031877 A1 WO2009031877 A1 WO 2009031877A1 MX 2008000118 W MX2008000118 W MX 2008000118W WO 2009031877 A1 WO2009031877 A1 WO 2009031877A1
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Prior art keywords
pharmaceutical composition
acemetacin
diacerein
formulation
rheumatoid arthritis
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PCT/MX2008/000118
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English (en)
Spanish (es)
Inventor
Leopoldo de Jesús ESPINOSA ABDALA
María Elena GARCÍA ARMENTA
Josefina Santos Murillo
Victor Guillermo ÁLVAREZ OCHOA
Original Assignee
Espinosa Abdala Leopoldo De Je
Garcia Armenta Maria Elena
Josefina Santos Murillo
Alvarez Ochoa Victor Guillermo
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Application filed by Espinosa Abdala Leopoldo De Je, Garcia Armenta Maria Elena, Josefina Santos Murillo, Alvarez Ochoa Victor Guillermo filed Critical Espinosa Abdala Leopoldo De Je
Priority to EP08829590A priority Critical patent/EP2218454A1/fr
Priority to BRPI0816263A priority patent/BRPI0816263A2/pt
Priority to ARP080103902A priority patent/AR068383A1/es
Publication of WO2009031877A1 publication Critical patent/WO2009031877A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention has application in the pharmaceutical industry and describes a pharmaceutical composition comprising the synergistic combination of a non-steroidal anti-inflammatory agent, such as the active ingredient: Acemetacin; a centrally acting muscle relaxant agent, such as the active substance: Methocarbamol and a selective inhibitor of Interleukin-1, as is the active substance: Diacerein; in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of rheumatoid arthritis and related diseases.
  • a pharmaceutical composition comprising the synergistic combination of a non-steroidal anti-inflammatory agent, such as the active ingredient: Acemetacin; a centrally acting muscle relaxant agent, such as the active substance: Methocarbamol and a selective inhibitor of Interleukin-1, as is the active substance: Diacerein; in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of r
  • the combination of the aforementioned active ingredients produces a greater synergistic effect when they are administered in combination in a single dosage unit unlike when they are administered independently, generating benefits such as: lower concentrations of the active ingredients contained in the formula, lower doses administered, faster pharmacological action and maximization of the therapeutic effect in less time, in addition to lower risks of side effects.
  • RA Rheumatoid Arthritis
  • Rheumatoid arthritis is one of the more than 100 existing rheumatic diseases with a specific prognosis and treatment, so the diagnosis must be accurate (usually made or confirmed by a rheumatologist).
  • RA is common, since in our environment it is suffered by one in 200 people. It is more common in women, but it also affects men. It is not a disease of old age and although it may appear in the elderly, it occurs more frequently in individuals between 45 and 55 years. Also, a very similar form of arthritis can affect children.
  • the joints are the structures that bind the bones and allow the mobility of the human body. The final portions of the bones have smooth surfaces that are the cartilage, which allow a smooth friction between said bones. In order to nourish and protect these bone endings coated with cartilage, the joints have a membrane (the membrane synovial) that covers them inside joining one bone with the other.
  • RA is a disease in which inflammation of the synovial membrane of multiple joints occurs. This inflammation will be responsible for the pain, swelling and stiffness that can be noticed in the morning. Some joints are affected more than others and there are some that almost never alter.
  • the persistence of inflammation of the synovial membrane determines that the area of the bone in which the synovial membrane is fixed is damaged, resulting in small notches (erosions).
  • the sustained inflammation of a joint causes the cartilage, which allows smooth friction between the bones, thins and disappears.
  • rheumatoid nodules can be found on the skin, which are hard lumps (nodules) that appear in areas of friction, such as: the elbows, the backs of the fingers and toes, the back of the head, heel area, etc. They can also be located inside the body, although rarely produce lesions of relevance to health. These nodules are the consequence of disease activity. Many times they disappear spontaneously or with treatment, although sometimes they have to be removed with surgery.
  • RA can cause inflammation and atrophy of the glands that produce tears, saliva, digestive juices or vaginal discharge. When this occurs, we talk about Sjógren's syndrome secondary to RA. RA can cause inflammation or other type of lesion in various structures of the organism, as well as alterations in blood and urine tests.
  • RA occurs more frequently in people with a special predisposition; However, it is not an inherited disease. The cause is unknown.
  • Various infectious agents bacteria, viruses have been studied and although suggestive data have been found in some cases, there is no evidence to confirm the involvement of one in particular.
  • RA does not currently have a curative treatment; However, this does not mean that there is no treatment. New medications appear that allow controlling the disease in an increasingly high percentage of patients.
  • RA non-steroidal anti-inflammatory drugs
  • glucocorticoids glucocorticoids
  • Nonsteroidal anti-inflammatory drugs are effective medications.
  • the other large group is the so-called disease-modifying drugs. These medications work by making the disease activity in the long term less. It takes weeks and even months to take effect. They are not effective in 100% of patients, so it is common that several should be prescribed sequentially until you find the one that is most effective and best tolerated. In this group are: Methotrexate, sulfazalazine, salts of gold, chloroquine, cyclosporine, D-penicillamine, azatrioprine, etc.
  • new disease-modifying drugs include multiple drugs that act at the level of TNF (tumor necrosis factor); This factor is recognized as a pathogenic molecule in RA, since by blocking TNF in patients with RA, joint damage has been shown to be significantly delayed.
  • TNF tumor necrosis factor
  • RA is a chronic polyarthritis that leads to bone destruction and severe joint dysfunction.
  • RA therapy with slow-acting antirheumatic disease-modifying drugs such as Methotrexate, is generally accepted as a standard long-term treatment, since it provides a significant reduction in symptoms, but does not stop cartilage destruction.
  • Glucocorticoids which are the most potent and important immunosuppressants, are used for the control of acute and severe joint inflammation, but are not used for chronic therapy in most patients, since they manifest significant adverse events.
  • the new therapeutic agents such as: monoclonal antibodies, human cytokine receptor immunoglobulin builders or recombinant human proteins, have been tested in RA and other chronic arthritic diseases, such as ankylosing spondylitis or psoriatic arthritis, with convincing evidence. of success.
  • the Clinical studies testing anti-TNF agents either alone or in combination with methotrexate, have provided feasibility and efficacy in these new approaches.
  • therapy that is aimed at inhibiting TNF and IL-I is clinically effective in only 40 to 70% of patients, and importantly they are TNF antagonist therapies that are associated with adverse events including: tuberculosis, listeriosis , lymph nodes and histoplasmosis. The numbers are not high, but clinical surveillance is necessary to minimize the risks.
  • osteoclasts such as osteoprotegerin
  • Rheumatoid arthritis is a disease with a very wide and varied spectrum, ranging from the mildest forms of the disease that require poor treatment and are compatible with a completely normal life, to the most severe forms of it that can shorten the life expectancy of the patient, especially if other pathologies occur accompanying said disease, which further complicates the existing clinical picture.
  • the disease left to its evolution without treatment has a poor prognosis and ends producing a significant functional deterioration of the affected joints.
  • Non-steroidal anti-inflammatory agents encompass a broad group of drugs that possess an important analgesic, anti-inflammatory and antipyretic activity, in addition to other therapeutic effects.
  • ACIDS a) Salicylates (Acetylsalicylic acid); b) Enolics: Pyrazolones (Metamizol), Pyrazolydinediones (Phenylbutazone), Oxicams (Piroxicam and Meloxicam); c) Acetic: Indolastic (Indomethacin, Acemetacin), Pyrrolacetic (Ketorolac), Phenylacetic (Diclofenac), Pyranoindoacetic (Etodolac); d) Propionic (Naproxen, Ibuprofen); e) Anthranilic (Mefenamic Acid); f) Nicotinic (Clonixin).
  • NON ACIDS a) Sulfoanilides (Nimesulide); b) Alcanones (Nabumetone); c) Paraaminophenols (Paracetamol).
  • COXIB Selective COX-2 inhibitors
  • Non-steroidal anti-inflammatories manifest their analgesic action by relieving pain associated with inflammation or tissue injury by decreasing the production of prostanoids that sensitize nociceptors to mediators, such as bradykinin. They are effective in pain of mild or moderate intensity. Its antipyretic effect is presented by inhibition of prostaglandin production in the hypothalamus and interference in temperature regulation mechanisms.
  • non-steroidal anti-inflammatories are analgesic and antipyretic, some ⁇ indomethacin, piroxicam) are more anti-inflammatory, most are moderately anti-inflammatory (ibuprofen, nabuwetone) and others ⁇ paracetamol) have minimal anti-inflammatory effect.
  • Some non-steroidal anti-inflammatory agents have platelet antiaggregant activity, which is of special interest in the case of Acetylsalicylic Acid because of its irreversible inhibitory effect on platelet COX.
  • This NSAID is very useful in the prevention of coronary and cerebral thromboembolic accidents.
  • some NSAIDs have uricosuric action as a result of the inhibition of uric acid transport from the lumen of the renal tubule to the interstitial space. It can only be seen with some NSAIDs at high doses, such as phenylbutazone, sulfinpyrazone or salicylates.
  • NSAIDs In the mechanism of action of NSAIDs, all their effects are related to the inhibition of cyclooxygenase (COX) and the inhibition of prostaglandin production.
  • COX cyclooxygenase
  • the ASA is the only one that produces an irreversible inhibition of COX-I.
  • the anti-inflammatory effect of NSAIDs is clearly related to COX-2 inhibition and many of undesirable effects are related to COX-I inhibition.
  • Acemetacin was carried out from the systematic alteration of the Indomethacin molecule through changes in the ⁇ -methyl group of indole-3-acetic acid, in the carboxyl group and replacement in the fundamental structure of indole with rings complementary heterocyclics.
  • Acemetacina The fixation of Acemetacina to the human albumin, depends on the concentration of proteins, oscillates between 81.5 and 93.7%, with a fraction of availability of free combination of around 60%, which suggests that the manifestation of the effect of Acemetacina is more Quick. Renal clearance for more conjugated free indomethacin and Acemetacin was performed at 29.9 mL./min. (9 hours later) and 32.6 mL./min. (24 hours later), without being related to the route of administration. The mean terminal elimination half-period for Acemetacin was determined in 5.84 hours. This elimination suggests that the risk of accumulation of Acemetacin is not important.
  • Acemetacin is a weak inhibitor of prostaglandin synthesis, preferentially affects COX-2 and to a much lesser extent COX-I, this gives it the property of inhibiting the synthesis of prostaglandins related to the reaction inflammatory, but very little affects those related to cell physiology; In addition, it inhibits serotonin, bradykinin and histamine, which are known mediators of inflammation.
  • the potent inhibition of COX-2 and the weak inhibition of COX-I make Acemetacin have a low renal and gastric toxicity profile, but a powerful anti-inflammatory effect.
  • Acemetacin has an effect of inhibiting prostaglandins in some dose-dependent manner, mainly affecting PGE2, it being necessary that the concentration of Acemetacin that inhibits such synthesis is higher, which speaks of a lower potency of the Acemetacin to inhibit prostaglandins, this is related to the low incidence of lesions in the gastric mucosa.
  • CM Muscle contracture
  • Muscle contracture involves a nociceptive afferent conduction from the damaged tissue, stimulated by alpha-motor neurons, to the muscle, resulting in a painful tonic contraction of the affected muscle, creating a vicious circle, since the pain caused by spasm produces a greater nociceptive stimulus that, by exciting the alpha-motor neurons, causes more spasm and more pain.
  • the pathophysiology of muscle contractures also includes dysfunction of descending pathways (corticospinal, vestibular, reticular, spinal) that exert control over alpha-motor neurons.
  • the peripheral reflex arcs although they are hyperactive due to the abnormal control that they receive from the upper nerve centers, apparently do not intervene in the pathological process; however, some sites on which these arcs influence, which include afferent nerve fibers from the skin and muscle spindles, spinal cord interneurons, efferent nerve fibers, and intrafusal and extrafunctional muscle fibers, are usually white for pharmacological intervention. You should control the increase in muscle tone.
  • the physical-sports activity causes a good number of situations that cause pain of the musculoskeletal system. Apart from the circumstances due to joint and bone lesions, the presence of local pains in the muscle masses occupies a prominent place within the main causes of medical consultation.
  • Myalgia is very imprecise, and therefore, sometimes we talk about cramps, contractures, spasms and a series of terms that sometimes do not end up defining specific situations. Other times the origin of the lesion allows greater specificity and there is talk of fibrillary rupture or bruise, recognizing a specific trauma as a cause of muscle pain.
  • Muscle processes that present with pain have an intimate substrate of inflammation or local interstitial edema.
  • the fact that there is often an increase in tissue tension or contracture means that, in general, medical treatment in these situations requires the use of muscle relaxants along with analgesics or anti-inflammatories.
  • Sports practice involves multiple situations of muscle pain due to traumatic, microtraumatic or overload aggressions.
  • the varied causes range from acute trauma that injures by its intensity, to small effort that injures because the muscle is fatigued or overloaded.
  • pain is spontaneously present on palpation and with muscle function.
  • Skeletal muscle relaxant drugs are used for the treatment of pathological processes associated with muscle contractures and have as their main objective to normalize muscle excitability without profoundly affecting motor function. Muscle relaxants should not avoid contraction, but normalize excitability and muscle tone to reduce pain and improve motor function.
  • Metocarbamol is an analog carbamate derived from Mefenesin that produces inhibition of polysynaptic reflexes, which acts as a centrally acting muscle relaxant.
  • Metocarbamol occurs within the first 30 minutes after being administered orally, achieving its maximum effect after 3 to 4 hours after its administration, with a total duration of its action therapeutic about 24 hours. Its half-life is approximately 14 hours.
  • Metocarbamol is absorbed almost completely after being administered orally; it is metabolized by dealkylation and hydroxylation and its elimination is carried out primarily through the urine as glucuronide and sulfate conjugates of its metabolites, only a small amount of it is excreted in the feces.
  • the mechanism of action of Metocarbamol has not yet been well established; However, the results of animal research have shown that it works by reducing polysynaptic reflex activity in the spinal cord, and it is through this mechanism that it reduces the excitability of alpha-motor neurons, resulting in muscle relaxation. skeletal; It also has a depressing effect on the central nervous system, resulting in a state of sedation that is largely due to the muscle relaxant effect.
  • Metocarbamol orally is up to 1.5 g four times a day, then reduced to a maintenance dose of 4 g per day for 2 to 3 days. It has been ensured that a dose of 750 mg three times a day is sufficient to have effective therapeutic effect.
  • Metocarbamol can also be administered intramuscularly with doses up to 500 mg every 8 hours; intravenously at a dose of 300 mg per minute by slow injection or by infusion in sodium chloride or glucose.
  • the parenteral dose should not exceed 3 g daily for 3 days.
  • Selective inhibitors of Interleukin-1 act by blocking the activity of Interleukin-1 that is produced by monocytes and macrophages as an early response of the immune system, stimulating T-cell proliferation and protein synthesis.
  • the body's immune system which normally confers protection against harmful external influences, may react erroneously. Sometimes, the immune system does not recognize the body's tissues as its own and destroys them causing diseases. Among these "autoimmune diseases” is rheumatoid arthritis.
  • Cytokines are messenger molecules with whose help cells communicate with each other.
  • the defective immune system produces excess cytokines that favor inflammation.
  • One of the crucial cytokines in the process of the appearance of rheumatoid arthritis is a cytokine called Interleukin-1 (IL-I).
  • Interleukin-1 is released by emitting cells and binds to specific receptors. This union produces a series of reactions.
  • the immune system induces the formation of IL-I in the synovial membrane; being there where Interleukin-1 causes inflammation and destruction of cartilage and bone.
  • Interleukin-1 is a molecule of glycoprotein nature, found in two active biological forms, IL-lalfa (IL-l ⁇ ) and IL-lbeta
  • IL-l ⁇ Both interleukins bind to the same receptor, despite not sharing much homology in the amino acid sequence (22%).
  • IL-IRa antagonist of the IL-I receptor
  • the three molecules constitute the family of IL-I.
  • the genes that code for each of the members of this family are located on the long arm of chromosome 2, where the genes for the two types of receptors that bind to IL-I are also located.
  • the immune system produces opposing molecules called antagonists, which bind to the receptor preventing the binding of Interleukin-1.
  • antagonists In the healthy joint there is a sufficient amount of antagonists that control the inflammatory process.
  • Interleukin-1 In rheumatoid arthritis there is an imbalance between Interleukin-1 and its antagonist, this is because in the joint there is a very high amount of Interleukin-1 and very little amount of antagonist. Consequently, Interleukin-1 disproportionately occupies many receptor sites, thus maintaining the inflammatory and destructive process in the joints.
  • Diacerein is a purified compound with anthraquinonic structure, which has inhibitory activity in vitro and in vivo on the production and activity of Interleukin-1 and the secretion of metalloproteases without altering the synthesis of prostaglandins, exerting a remodeling mechanism of articular cartilage .
  • Diacerein has proven effective in the treatment of osteoarthritis (OA), a degenerative joint process that is characterized by progressive destruction and erosion of cartilage.
  • OA osteoarthritis
  • the oral administration of Diacerein to patients with OA of the hip was associated with a symptomatic improvement and a modifying effect of the cartilage structure, accompanied by a good safety profile.
  • Interleukin-1 is a factor that is involved in the macrophage-neutrophil response to inflammation and plays an important role in the degradation of articular cartilage. This factor together with TNF (Tumor Necrosis Factor) and other colony stimulating factors produces a feedback mechanism that begins with tissue inflammation, continuing with the formation of leukocytes.
  • TNF Tumor Necrosis Factor
  • Diacerein Inhibits the production of Interleukin-1 and decreases collagenolytic activity.
  • Diacerein The antiarthrotic properties of Diacerein are due to its ability to inhibit pro-inflammatory and pro-catabolic cytokines, such as Interleukin-1, which plays an important role in the degradation of articular cartilage, as well as in the inhibition of production and release of enzymes that degrade cartilage (collagenase and stromelysin).
  • pro-inflammatory and pro-catabolic cytokines such as Interleukin-1
  • Interleukin-1 which plays an important role in the degradation of articular cartilage, as well as in the inhibition of production and release of enzymes that degrade cartilage (collagenase and stromelysin).
  • Diacerein is hydrolyzed before entering the systemic circulation and undergoes a hepatic first-pass metabolism, being completely deacetylated and becoming queen form and its conjugates. Simultaneous ingestion of Diacerein with food It causes a delay in its absorption by prolonging the tmax, while increasing its bioavailability. The queen binds to plasma proteins in 99%. Its excretion is by the renal route in the form of queen and its conjugates (glucuronides and sulfates). The elimination half-life of plasma Diacerein is 5 to 7 hours.
  • Diacerein has a slow onset of action that does not become significant until after 4 weeks of treatment. The effect is maintained for at least 2 months after stopping treatment.
  • the development of the present pharmaceutical composition was carried out, which is composed of the synergistic combination of a non-steroidal anti-inflammatory agent, such as the active substance: Acemetacin, a centrally acting muscle relaxant agent, such as the active substance: Metocarbamol and a selective inhibitor of Interleukin-1, such as the active substance: Diacerein, in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally.
  • a non-steroidal anti-inflammatory agent such as the active substance: Acemetacin
  • a centrally acting muscle relaxant agent such as the active substance: Metocarbamol
  • a selective inhibitor of Interleukin-1 such as the active substance: Diacerein
  • Said formulation has been developed considering that the active ingredients contained in the pharmaceutical composition object of the present invention have an important potency and efficacy to avoid or reduce the presence of the inflammatory and / or painful processes that usually accompany this disease, in addition to modifying the course of it, preventing its progression, also providing faster pharmacological action and maximizing its therapeutic effect in less time, as well as reducing risks that side effects manifest.
  • the non-steroidal anti-inflammatory agent used in the pharmaceutical composition object of the present invention such as the active ingredient: Acemetacin, is present in the formulation in a concentration range from 30.0 mg to 180.0 mg per dose unit.
  • the centrally acting muscle relaxant agent used in the pharmaceutical composition object of the present invention such as the active ingredient: Metocarbamol, is present in the formulation in a concentration range from 100.0 mg to 850.0 mg per dose unit.
  • the selective inhibitor of Interleukin-1 used in the pharmaceutical composition object of the present invention such as the active ingredient: Diacerein, is present in the formulation in a concentration range from 25.0 mg to 100.0 mg per dose unit.
  • Diacerein in a single dosage unit a comparative clinical study was conducted in which the active ingredients mentioned above were administered separately, as well as the combination thereof.
  • the 50 patients were divided into two treatment groups: -Group 1: received treatment of Acemetacin 90 mg every 12 hours, Metocarbamol 215 mg every 12 hours and Methotrexate 2.5 mg every 3rd. day. -Group 2: received treatment of Acemetacina / Metocarbamol / Diacereina twice a day, during 6 weeks of follow-up.
  • Nonsteroidal anti-inflammatory drugs are used to control the symptoms of RA; therapy with slow-acting antirheumatic disease modifying drugs, such as Methotrexate, which is accepted as a standard long-term treatment, leads to a reduction in symptoms but does not stop the destruction of cartilage.
  • Metocarbamol is used as an adjuvant for the prevention and / or treatment of muscle contracture.
  • Acemetacin and Diacerein which are well tolerated effective therapeutic agents, clearly demonstrates that This composition has an important antiarthritic activity, preventing from the beginning of the disease the manifestation of the inflammatory and painful processes that are associated with Rheumatoid Arthritis, in addition to causing the suppression of the progression of joint pathology.
  • the preservation of the articular architecture after the administration of the combination Acemetacina + Metocarbamol + Diacereina is mainly due to the suppression of the high proliferation of the synovial tissue, also called pannus, which is composed of myelomonocytic synoviocytes, such as synovial monocytes and macrophages, and mesenchymal synoviocytes, such as synovial fibroblasts, in addition to various infiltrating inflammatory cells, which contribute to the invasion and destruction of cartilage and joint bone.
  • synovial tissue also called pannus
  • myelomonocytic synoviocytes such as synovial monocytes and macrophages
  • mesenchymal synoviocytes such as synovial fibroblasts

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Abstract

La présente invention concerne une composition pharmaceutique comprenant une combinaison synergique d'un anti-inflammatoire non stéroïdien connu sous le nom d'acémétacine, d'un myorelaxant à action centrale connu sous le nom de méthocarbamol, et d'un inhibiteur sélectif de l'interleukine 1 connu sous le nom de diacéréine, ainsi que des excipients pharmaceutiquement acceptables, lesdits ingrédients étant formulés en une seule dose unitaire en vue d'une administration par voie orale. Cette composition est utilisée pour contrôler et traiter l'arthrite rhumatoïde et les maladies associées, et permet d'obtenir une action pharmacologique plus rapide et une maximisation de l'effet thérapeutique sur une durée réduite. Elle permet en outre de réduire l'inflammation et la douleur et de modifier le cours de la maladie, diminuant ainsi le risque d'effets secondaires.
PCT/MX2008/000118 2007-09-07 2008-09-05 Composition pharmaceutique comprenant une combinaison d'acémétacine, de méthocarbamol et de diacéréine, utile dans le traitement de l'arthrite rhumatoïde et des maladies associées WO2009031877A1 (fr)

Priority Applications (3)

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EP08829590A EP2218454A1 (fr) 2007-09-07 2008-09-05 Composition pharmaceutique comprenant une combinaison d'acémétacine, de méthocarbamol et de diacéréine, utile dans le traitement de l'arthrite rhumatoïde et des maladies associées
BRPI0816263A BRPI0816263A2 (pt) 2007-09-07 2008-09-05 composição farmacêutica que compreende a combinação de acemetacina, metocarbamol e diacereína, útil no tratamento da artrite reumatóide e doenças relacionadas
ARP080103902A AR068383A1 (es) 2007-09-07 2008-09-08 Composicion farmaceutica que comprende la combinacion de un antiinflamatorio no esteroideo , un relajante muscular de accion central y un inhibidor de la interleucina -1, indicada para el tratamiento de la artritis reumatoide y enfermedades relacionadas

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXMX/A/2007/011003 2007-09-07
MX2007011003A MX2007011003A (es) 2007-09-07 2007-09-07 Composicion farmaceutica que comprende la combinacion de un antiinflamatorio no esteroideo, un relajante muscular de accion central y un inhibidor de la interleucina-1, indicada para el tratamiento de la artritis reumatoide y enfermedades relacionada

Publications (1)

Publication Number Publication Date
WO2009031877A1 true WO2009031877A1 (fr) 2009-03-12

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PCT/MX2008/000118 WO2009031877A1 (fr) 2007-09-07 2008-09-05 Composition pharmaceutique comprenant une combinaison d'acémétacine, de méthocarbamol et de diacéréine, utile dans le traitement de l'arthrite rhumatoïde et des maladies associées

Country Status (10)

Country Link
EP (1) EP2218454A1 (fr)
AR (1) AR068383A1 (fr)
BR (1) BRPI0816263A2 (fr)
CL (1) CL2008002664A1 (fr)
CO (1) CO6260067A2 (fr)
EC (1) ECSP10010010A (fr)
GT (1) GT201000052A (fr)
MX (1) MX2007011003A (fr)
PE (1) PE20091200A1 (fr)
WO (1) WO2009031877A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0265858A1 (fr) * 1986-10-29 1988-05-04 L.B.S. S.r.l. LABORATORIO BIOCHIMICO SPERIMENTALE Compositions antiinflammatoires topiques
EP1655026A1 (fr) * 2004-10-04 2006-05-10 Espinosa Abdala, Leopoldo Composition pharmaceutique solide comprénant diacerein et meloxicame
WO2007037666A1 (fr) * 2005-09-29 2007-04-05 World-Trade Import-Export, Wtie, Ag. Forme pharmaceutique contenant du metocarbamol, du meloxicam et de la betamethasone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0265858A1 (fr) * 1986-10-29 1988-05-04 L.B.S. S.r.l. LABORATORIO BIOCHIMICO SPERIMENTALE Compositions antiinflammatoires topiques
EP1655026A1 (fr) * 2004-10-04 2006-05-10 Espinosa Abdala, Leopoldo Composition pharmaceutique solide comprénant diacerein et meloxicame
WO2007037666A1 (fr) * 2005-09-29 2007-04-05 World-Trade Import-Export, Wtie, Ag. Forme pharmaceutique contenant du metocarbamol, du meloxicam et de la betamethasone

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBMED [online] Database accession no. 2529083 *
GOSPODINOFF A. ET AL.: "Open clinical study on the efficacy and tolerance of acemetacin in rheumatoid arthritis and osteoarthrosis", LA CLINICA TERAPEUTICA, vol. 130, no. 2, 1989, pages 109 - 113, XP008132272 *

Also Published As

Publication number Publication date
PE20091200A1 (es) 2009-08-26
EP2218454A1 (fr) 2010-08-18
CO6260067A2 (es) 2011-03-22
MX2007011003A (es) 2009-03-09
AR068383A1 (es) 2009-11-11
ECSP10010010A (es) 2010-04-30
GT201000052A (es) 2015-03-25
CL2008002664A1 (es) 2009-04-03
BRPI0816263A2 (pt) 2019-09-24

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